Oncology Intelligence

Pharyngeal Cancer
Oral squamous cell carcinoma (OSCC) is the sixth most common cancer worldwide. OSCC falls into a larger category known as head and neck squamous cell carcinomas (HNSCCs). This collection constitutes all squamous cell carcinomas of the oral cavity, larynx, pharynx and oesophagus of which OSCC is the most common. Cancer cells involve morphological cellular transformation, dysregulation of apoptosis, uncontrolled cellular proliferation, invasion, angiogenesis, and metastasis. Also, one of the hallmarks of cancer is the elevated uptake of glucose even under normal oxygen conditions, known as aerobic glycolysis or the “Warburg effect”. The Warburg effect is the cellular phenomenon in which the tumor cells primarily use glycolysis for energy production instead of mitochondrial oxidative phosphorylation like normal cells. These cellular responses have been shown to cause distinct transformations like the upregulation of proteins such as hypoxia-inducible factor 1-α that help the tumor survive adverse conditions in which normal cells cannot persist. HIF-1α stimulates transcriptional induction of a series of genes that participate in iron metabolism, glucose metabolism, cell proliferation / survival and angiogenesis.
Sunday, September 18, 2016 10:27 AM|Head and Neck Oncology|Labels: HIF, pharyngeal
Objective: the aim of this study is to assess whether C1772T and G1790A HIF-1α polymorphisms are associated with odds ratio of OSCC development. Materials and Methods:restriction fragment length polymorphism (RFLP) analysis was used to investigate HIF-1α C1779T and G1790A polymorphisms in 48 patients with epithelial dysplasia (ED) and 40 patients with oral squamous cell carcinoma (OSCC). Additionally, 88 elderly individuals without HNSCC were enrolled as a control group. Results: the frequency of the TT, GA, and AA genotypes was higher in patients with ED and OSCC when compared with controls. However, CT genotype was associated with moderate epithelial dysplasia in ED patients, while TT genotype was more frequent in OSCC patients. Conclusions: In conclusion, our study demonstrated that the T and A alleles of C1772T and G1790A polymorphisms of the HIF-1α gene increased the risk of ED and OSCC. C1772T and G1790A polymorphisms of the HIF-1α gene had differing patterns of allelic imbalance in the precancerous lesions and subsequent carcinoma, suggesting a complex genetic pattern of progression from dysplasia to carcinoma. These findings suggest an additional role for HIF-1α in OSCC development. Further studies are necessary to elucidate the HIF-1α pathway in carcinogenesis, which would facilitate the development of novel therapeutic strategies for the prevention and treatment of OSCC and other solid tumors
Sunday, September 18, 2016 10:27 AM|Head and Neck Oncology|Labels: pharyngeal
Trismus is often present in patients diagnosed with oral malignancy. Trismus is a debilitating condition and is treated adequately with release of fibrosis and interposition of vascularised tissue to provide long term improvement in mouth opening. Treatment of an oral cancer in a patient with trismus becomes challenging because of difficult access and further deterioration of mouth opening following treatment of the malignancy. Herein we describe the planning of access and management of oral carcinoma with severe trismus using nasolabial flaps.
Sunday, September 18, 2016 10:27 AM|Head and Neck Oncology|Labels: pharyngeal
Oral and pharyngeal cancers are the sixth most common cancers internationally. In the United States, there are about 30,000 new cases of oral and pharyngeal cancers diagnosed each year. Furthermore, survival rates for oral and pharyngeal cancers have not significantly improved over the last three decades. This review examines the scientific literature surrounding the epidemiology of oral and pharyngeal cancers, including but not limited to risk factors, disparities, preventative factors, and the epidemiology in countries outside the United States. The literature review revealed that much of the research in this field has been focused on alcohol, tobacco, and their combined effects on oral and pharyngeal cancers. The literature on oral and pharyngeal cancer disparities among racial groups also appears to be growing. However, less literature is available on the influence of dietary factors on these cancers. Finally, effective interventions for the reduction of oral and pharyngeal cancers are discussed.
Sunday, September 18, 2016 10:27 AM|Head and Neck Oncology|Labels: pharyngeal
Factors that represent the potential for invasion and metastasis, such as matrix metalloproteinases (MMPs), could predict prognosis of cancer. Although an important risk factor for oral cancer is the presence of epithelial dysplasia, many lesions will not progress to malignancy. Matrix metalloproteinases (MMPs) are zinc dependent proteinases capable of digesting various structural components of the extracellular matrix. Because MMPs are frequently overexpressed in Oral squamous cell carcinoma (SCC), we found that they are also overexpressed in oral dysplasias which is restricted to the epithelium though; we also found that those dysplasias that progress to oral cancer express higher levels of MMPs than those lesions that do not progress. Also, it was observed that as the expression of MMP-2 and MMP-9 increased the prognosis became poorer. Hence, we conclude that as the expression of MMP-2 and MMP-9 increases in Epithelial dysplasia, Verrucous carcinoma and OSCC the survival rate decreases.
Sunday, September 18, 2016 10:27 AM|Head and Neck Oncology|Labels: pharyngeal
Introduction. Human podoplanin has a role in the invasion process of the epithelial malignant cells and its upregulation is correlated with poor prognosis in patients with head and neck cancer. The cytoplasmic tail of the podoplanin can bind to ezrin, a protein that have been associated with metastasis and lower survival rate in patients with oral cancer. The aim of this study was to evaluate the association between podoplanin and ezrin immunoexpressions by the cells of the invasive tumor front in the lip cancer. Method. 48 squamous cell carcinomas arising in the inferior lip were immunohistochemically investigated for the membranous and cytoplasmic expressions of podoplanin and ezrin in peripheral and central areas of the tumor front. The association between the membranous and cytoplasmic expression of podoplanin and ezrin by malignant cells was evaluated by chi-square test and Spearman’s correlation coefficient with a significance level of 5% for both tests. Results.The results showed a strong membranous and cytoplasmic podoplanin expression by peripheral cells of the invasive tumor front, with no expression of this protein by central cells. The ezrin immunostaining was homogeneous and mainly observed in the cytoplasm of malignant cells. A statistically significant difference was found between the expression of podoplanin in peripheral and central tumor cells (p<0,001). The cytoplasmic expression of ezrin was higher than membranous (p<0.001) in squamous cell carcinoma of the lip. There was not a statistical significant correlation between the expression of membranous podoplanin and membranous or cytoplasmic ezrin by peripheral tumor cells. Conclusion.The interpretation of our results reinforce that the tumor cells in the invasive front tumor expressed strongly both podoplanin (membranous and cytoplasmic) as cytoplasmic ezrin and it suggests a participation of these proteins in the process of invasion in lip cancer.
Sunday, September 18, 2016 10:27 AM|Head and Neck Oncology|Labels: pharyngeal
The increased understanding of the molecular basis of oral cancer has led to expectations that correction of the genetic defects will lead to improved treatments. Nevertheless, the first clinical trials for gene therapy of oral cancer occurred 20 years ago, and routine treatment is still not available. The major difficulty is that genes are usually delivered by virus vectors whose effects are weak and temporary. Viruses that replicate would be better, and the field includes many approaches in that direction. If any of these are effective in patients, then gene therapy will become available in the next few years. Without significant advances, however, the treatment of oral cancer by gene therapy will remain as remote as the legendary pot of gold at the end of the rainbow.
Sunday, September 18, 2016 10:27 AM|Head and Neck Oncology|Labels: pharyngeal
Recently, more evidence has been presented for the potential anti-cancer effect of metformin, a drug used successfully to treat diabetes mellitus Therefore, the aim of this study was twofold: to compare diabetic patients with oral cancer who were treated with metformin to non-diabetic patients with oral cancer who did not receive metformin treatment, and to provide a review of the current literature in regard to oral cancer. Patients and Methods Files of all patients treated for oral cancer at the Department of Craniomaxillofacial and Oral Surgery, University Hospital Zurich between January 2007 and August 2012 were evaluated retrospectively. Age, gender distribution, and presence of metformin-treated, type 2 diabetes were taken into consideration. Results A total of 154 patients were treated (91 male and 63 female); their median age was 63.7 years (24-89 years). Six patients (3.9%) had diabetes; of those, 2 (1.3%) were treated with insulin and 4 (2.6%) with metformin. Conclusion A lower prevalence of oral cancer was found in diabetic patients being treated with metformin, but further studies need to be performed with a larger population.
Friday, September 16, 2016 10:23 AM|Chia-Ing Jan, Ming-Hsui Tsai, Chang-Fang Chiu, Yi-Ping Huang, Chia Jen Liu, Nai Wen Chang|International Journal of Biological Sciences|Labels: AKT, mTOR, pharyngeal

One anticancer strategy suggests targeting mitochondrial metabolism to trigger cell death through slowing down energy production from the Warburg effect. Fenofibrate is a clinical lipid-lowering agent and an effective anticancer drug. In the present study, we demonstrate that fenofibrate provided novel mechanisms for delaying oral tumor development via the reprogramming of metabolic processes. Fenofibrate induced cytotoxicity by decreasing oxygen consumption rate (OCR) that was accompanied with increasing extracellular acidification rate (ECAR) and reducing ATP content. Moreover, fenofibrate caused changes in the protein expressions of hexokinase II (HK II), pyruvate kinase, pyruvate dehydrogenase, and voltage-dependent anion channel (VDAC), which are associated with the Warburg effect. In addition, fenofibrate reprogrammed the metabolic pathway by interrupting the binding of HK II to VDAC. In an oral cancer mouse model, fenofibrate exhibited both preventive and therapeutic efficacy on oral tumorigenesis. Fenofibrate administration suppressed the incidence rate of tongue lesions, reduced the tumor sizes, decreased the tumor multiplicity, and decreased the immunoreactivities of VDAC and mTOR. The molecular mechanisms involved in fenofibrate's ability to delay tumor development included the down-regulation of mTOR activity via TSC1/2-dependent signaling through activation of AMPK and inactivation of Akt, or via a TSC1/2-independent pathway through direct suppression of raptor. Our findings provide a molecular rationale whereby fenofibrate exerts anticancer and additional beneficial effects for the treatment of oral cancer patients.

Thursday, September 15, 2016 7:51 PM|Chia Ee Lee, Vui King Vincent-Chong, Anand Ramanathan, Thomas George Kallarakkal, Lee Peng Karen-Ng, Wan Maria Nabillah Ghani, Zainal Ariff Abdul Rahman, Siti Mazlipah Ismail, Mannil Thomas Abraham, Keng Kiong Tay, Wan Mahadzir Wan Mustafa, Sok Ching Cheong, Rosnah Binti Zain|International Journal of Medical Sciences|Labels: pharyngeal

BACKGROUND: Collagen Triple Helix Repeat Containing 1 (CTHRC1) is a protein often found to be over-expressed in various types of human cancers. However, correlation between CTHRC1 expression level with clinico-pathological characteristics and prognosis in oral cancer remains unclear. Therefore, this study aimed to determine mRNA and protein expression of CTHRC1 in oral squamous cell carcinoma (OSCC) and to evaluate the clinical and prognostic impact of CTHRC1 in OSCC.

METHODS: In this study, mRNA and protein expression of CTHRC1 in OSCCs were determined by quantitative PCR and immunohistochemistry, respectively. The association between CTHRC1 and clinico-pathological parameters were evaluated by univariate and multivariate binary logistic regression analyses. Correlation between CTHRC1 protein expressions with survival were analysed using Kaplan-Meier and Cox regression models.

RESULTS: Current study demonstrated CTHRC1 was significantly overexpressed at the mRNA level in OSCC. Univariate analyses indicated a high-expression of CTHRC1 that was significantly associated with advanced stage pTNM staging, tumour size ≥ 4 cm and positive lymph node metastasis (LNM). However, only positive LNM remained significant after adjusting with other confounder factors in multivariate logistic regression analyses. Kaplan-Meier survival analyses and Cox model demonstrated that patients with high-expression of CTHRC1 protein were associated with poor prognosis and is an independent prognostic factor in OSCC.

CONCLUSION: This study indicated that over-expression of CTHRC1 potentially as an independent predictor for positive LNM and poor prognosis in OSCC.

Thursday, September 15, 2016 6:45 AM|Facompre, N. D., Harmeyer, K. M., Sole, X., Kabraji, S., Belden, Z., Sahu, V., Whelan, K., Tanaka, K., Weinstein, G. S., Montone, K. T., Roesch, A., Gimotty, P. A., Herlyn, M., Rustgi, A. K., Nakagawa, H., Ramaswamy, S., Basu, D.|Cancer Research recent issues|Labels: AKT, PI3K, pharyngeal
The degree of heterogeneity among cancer stem cells (CSC) remains ill-defined and may hinder effective anti-CSC therapy. Evaluation of oral cancers for such heterogeneity identified two compartments within the CSC pool. One compartment was detected using a reporter for expression of the H3K4me3 demethylase JARID1B to isolate a JARID1Bhigh fraction of cells with stem cell–like function. JARID1Bhigh cells expressed oral CSC markers including CD44 and ALDH1 and showed increased PI3K pathway activation. They were distinguished from a fraction in a G0-like cell-cycle state characterized by low reactive oxygen species and suppressed PI3K/AKT signaling. G0-like cells lacked conventional CSC markers but were primed to acquire stem cell–like function by upregulating JARID1B, which directly mediated transition to a state expressing known oral CSC markers. The transition was regulated by PI3K signals acting upstream of JARID1B expression, resulting in PI3K inhibition depleting JARID1Bhigh cells but expanding the G0-like subset. These findings define a novel developmental relationship between two cell phenotypes that may jointly contribute to CSC maintenance. Expansion of the G0-like subset during targeted depletion of JARID1Bhigh cells implicates it as a candidate therapeutic target within the oral CSC pool. Cancer Res; 76(18); 5538–49. ©2016 AACR.
Tuesday, September 13, 2016 11:38 PM|Shuaimei Xu, Dandan Ma, Rui Zhuang, Wenjuan Sun, Ying Liu, Jun Wen, Li Cui|Journal of Cancer|Labels: pharyngeal

Background: The development of oral squamous cell carcinoma (OSCC) is a multistep process that involves in both genetic alterations and epigenetic modifications. DJ-1, a negative regulator of tumor suppressor PTEN, functions as an oncogene in many types of cancers. However, its role in OSCC is poorly known.

Methods: Immunohistochemical staining and Western blotting were performed to evaluate the expression level of DJ-1 in oral leukoplakia (OLK) and OSCC tissues respectively. Then lentiviral mediated DJ-1 shRNA was constructed and used to infect the OSCC cell lines (Tca8113 and CAL-27). MTT, cell counting, and Matrigel invasion assay were utilized to examine the effects of DJ-1 down-regulation on proliferation and invasion capacity of oral cancer cells.

Results: The immunoreactivity and expression level of DJ-1 protein was significantly increased in OLK and OSCC tissues compared with the controls. Lentiviral-delivered shRNA targeting DJ-1 could effectively knock down DJ-1 at mRNA and protein level (P<0.01). The proliferative and invasion ability of OSCC cell lines was significantly suppressed following DJ-1 inhibition (P<0.01).

Conclusions: Our study indicated that DJ-1 is over-expressed in both oral precancer and cancer tissues and shRNA inhibition of DJ-1 expression led to decreased proliferation and invasion capability of oral cancer cells. These findings suggest that DJ-1 might be actively involved in the development of OSCC. Future studies will investigate the potential of DJ-1 as a biomarker for early detection of OSCC.

Tuesday, September 13, 2016 11:38 PM|Lin Kong, Jiyi Hu, Xiyin Guan, Jing Gao, Rong Lu, Jiade J. Lu|Journal of Cancer|Labels: pharyngeal, clinical trial

Background: Radiation therapy is the mainstay strategy for the treatment of nasopharyngeal cancer (NPC). Intensity-modulated X-ray therapy (IMXT) alone is the current standard for stage I and II NPC. For stage III and IV A/B diseases, concurrent chemotherapy should be provided in addition to IMXT. However, optimal treatment for locally recurrent NPC after previous definitive dose of radiotherapy is lacking. Various techniques including brachytherapy, IMXT, stereotactic radiosurgery or radiotherapy (SRS or SBRT) have been used in the management of locally recurrent NPC. Due to the inherent limitation of these techniques, i.e., limited range of irradiation or over-irradiation to surrounding normal tissues, moderate efficacy has been observed at the cost of severe toxicities. Carbon ion radiotherapy (CIRT) offers potential physical and biological advantages over photon and proton radiotherapy. Due to the inverted dose profile of particle beams and their greater energy deposition within the Bragg peak, precise dose delivery to the target volume(s) without exposing the surrounding organs at risk to extra doses is possible. In addition, CIRT provides an increased relative biological effectiveness (RBE) as compared to photon and proton radiotherapy. Such advantages may translate to improved outcomes after irradiation in terms of disease control in radio-resistant and previously treated, recurrent malignancies. It is therefore reasonable to postulate that recurrent NPC after high-dose radiotherapy could be more resistant to re-irradiation using photons. Reports on the treatment of radio-resistant malignancies in the head and neck region such as melanoma, sarcoma, and adenoid cystic carcinoma (ACC) have demonstrated superior local control rates from CIRT as compared to photon irradiation. Thus patients with recurrent NPC are likely to benefit from the enhanced biological effectiveness of carbon ions. As effective retreatment strategy is lacking for locally recurrent NPC, carbon ion radiation therapy offers an ideal alternate to conventional X-ray irradiation.

Methods and Design: The recommended dose of re-irradiation using CIRT for locally recurrent NPC will be determined in the dose-escalating phase (Phase I) of the study. Efficacy in terms of local progression-free survival (LPFS) and overall survival (OS) will be studied in the second phase of the study. Increasing doses of CIRT using raster scanning technology from 55GyE (22×2.5 GyE) to 65 GyE (26× 2.5 GyE) will be delivered in the Phase I part of the study. The primary endpoint of the Phase I part of the study is acute and sub-acute toxicities; the primary endpoint in the Phase II part is local progression-free survival and overall survival. Using the historical 2-year OS rate of 50% in locally recurrent NPC patients treated with photon or proton, we hypothesize that CIRT can improve the 2-year OS rate to 70%.

Discussion: The utilization of conventional radiation techniques including IMXT, brachytherapy, or stereotactic radiation therapy provides moderate efficacy in the treatment of locally recurrent NPC due to the limitations in dose distribution and biological effectiveness. Improved outcome in terms of treatment-induced toxicity, LC, LPFS, and OS are expected using CIRT due to the physical and biological characteristics of carbon ion beam. However, the recommended dose of CIRT used in re-irradiation for the local NPC focus remain to be determined. The recommended dose as well as the efficacy of CIRT in the treatment of locally recurrent NPC will be evaluated in the present trial.

Tuesday, September 13, 2016 11:38 PM|Xiao-Jing Du, Ling-Long Tang, Yan-Ping Mao, Rui Guo, Ying Sun, Ai-Hua Lin, Jun Ma|Journal of Cancer|Labels: pharyngeal

Background: The optimal treatment for early-stage nasopharyngeal carcinoma (NPC) remains controversial. Identification of prognostic factors for metastasis and tumor progression is urgently required to improve clinical decision-making for patients with American Joint Committee on Cancer (AJCC) 2009 stage II NPC from the endemic area.

Methods: Consecutive newly-diagnosed patients (n=296) with non-disseminated, biopsy-proven stage II NPC were retrospectively reviewed; all patients received intensity-modulated radiotherapy and MRI follow-up. Plasma EBV DNA level, serum lactate dehydrogenase, serum albumin, serum globulin and leukocyte counts were measured before therapy. Survival rates were analyzed using the Kaplan-Meier method and log-rank test and multivariate Cox proportional hazards model.

Results: Median follow-up was 50.2 months (range, 8-69.5 months). Multivariate analysis demonstrated a plasma Epstein-Barr virus (EBV) DNA level ≥ 4000 copies/mL, maximal axial diameter (MAD) of the cervical lymph nodes ≥ 30 mm and serum globulin level < 29.5 g/L were independent predictors of poor DMFS (P = 0.018; P = 0.019; P = 0.006, respectively). On the basis of these parameters, a prognostic model was developed as follows: 1) patients with no risk factors; 2) one risk factor; and 3) two or three risk factors. The 3-year distant metastasis-free survival rates for groups 1, 2 and 3 were 100%, 94.6% and 84.3%, respectively (P = 0.001).

Conclusion: The prognostic model based on EBV DNA, serum globulin and nodal size may facilitate individualized treatment of patients with stage II NPC at high risk of distant metastasis.

Thursday, August 25, 2016 2:25 AM|Yong-Tao Yang, Yu-Fan Wang, Ju-Yi Lai, Shi-Yue Shen, Feng Wang, Jie Kong, Wei Zhang, Hong-Yu Yang|Cancer Science|Labels: WNT, pharyngeal
With the development of the functional genomics studies, a mass of long non-coding RNAs (LncRNA) were discovered from the human genome. LncRNAs serve as pivotal regulator of genes, which are able to generate LncRNA-binding-protein complexes to modulate a great many of genes. Recently, the LncRNA urothelial carcinoma-associated 1 (UCA1) has been revealed to be dysregulated, which plays a critical role in the development of a few cancers. However, the role of biology and clinical signification of UCA1 in the tumorigenesis of oral squamous carcinoma (OSCC) remain unknown. Hereof, we found that UCA1 expression levels were upregulated aberrantly in TSCC tissues and associated with lymph node metastasis (LNM) and TNM stage. We explored the expression, function and molecular mechanism of LncRNA-UCA1 in the oral squamous cell carcinoma. In the present work, we demonstrated that UCA1 silencing suppressived the proliferation and metastasis, induced apoptosis of OSCC cell lines in vitro and in vivo, which might be related to the activation level of WNT/β-catenin signaling pathway. To sum up, our research results emphasize the pivotal role of UCA1 in the oncogenesis of OSCC and, revealed a novel LncRNA UCA1-β-catenin-WNT signaling pathway regulatory network, which may contribute to our understanding in the pathogenesis of OSCC and discover a viable LncRNA-directed diagnostic and therapeutic strategy for this fatal disease. This article is protected by copyright. All rights reserved.
Sunday, August 14, 2016 10:05 PM|Stanford, E. A., Ramirez-Cardenas, A., Wang, Z., Novikov, O., Alamoud, K., Koutrakis, P., Mizgerd, J. P., Genco, C. A., Kukuruzinska, M., Monti, S., Bais, M. V., Sherr, D. H.|Molecular Cancer Research recent issues|Labels: pharyngeal

Over 45,000 new cases of oral and pharyngeal cancers are diagnosed and account for over 8,000 deaths a year in the United States. An environmental chemical receptor, the aryl hydrocarbon receptor (AhR), has previously been implicated in oral squamous cell carcinoma (OSCC) initiation as well as in normal tissue-specific stem cell self-renewal. These previous studies inspired the hypothesis that the AhR plays a role in both the acquisition and progression of OSCC, as well as in the formation and maintenance of cancer stem-like cells. To test this hypothesis, AhR activity in two oral squamous cell lines was modulated with AhR prototypic, environmental and bacterial AhR ligands, AhR-specific inhibitors, and phenotypic, genomic and functional characteristics were evaluated. The data demonstrate that: (i) primary OSCC tissue expresses elevated levels of nuclear AhR as compared with normal tissue, (ii) AhR mRNA expression is upregulated in 320 primary OSCCs, (iii) AhR hyperactivation with several ligands, including environmental and bacterial ligands, significantly increases AhR activity, ALDH1 activity, and accelerates cell migration, (iv) AhR inhibition blocks the rapid migration of OSCC cells and reduces cell chemoresistance, (v) AhR knockdown inhibits tumorsphere formation in low adherence conditions, and (vi) AhR knockdown inhibits tumor growth and increases overall survival in vivo. These data demonstrate that the AhR plays an important role in development and progression of OSCC, and specifically cancer stem-like cells. Prototypic, environmental, and bacterial AhR ligands may exacerbate OSCC by enhancing expression of these properties.

Implications: This study, for the first time, demonstrates the ability of diverse AhR ligands to regulate AhR activity in oral squamous cell carcinoma cells, as well as regulate several important characteristics of oral cancer stem cells, in vivo and in vitro. Mol Cancer Res; 14(8); 696–706. ©2016 AACR.

Sunday, July 31, 2016 10:05 PM|Peyser, N. D., Wang, L., Zeng, Y., Acquafondata, M., Freilino, M., Li, H., Sen, M., Gooding, W. E., Satake, M., Wang, Z., Johnson, D. E., Grandis, J. R.|Cancer Prevention Research recent issues|Labels: STAT, pharyngeal

Head and neck squamous cell carcinoma (HNSCC) is a frequently fatal disease due, in large part, to a high rate of second primary tumor (SPT) formation. The 4-nitroquinoline 1-oxide (4-NQO) mouse model of oral carcinogenesis provides a robust system in which to study chemopreventive agents in the context of chemically induced HNSCC tumors. STAT3 is a potent oncogene that is hyperactivated by tyrosine phosphorylation early in HNSCC carcinogenesis and is a rational therapeutic target. We recently reported that loss-of-function of the STAT3 phosphatase PTPRT promotes STAT3 activation in HNSCC tumors and preclinical models and may serve as a predictive biomarker of response to STAT3 inhibitors, including the small-molecule Stattic. We therefore investigated the hypothesis that Ptprt-knockout (KO) mice would be more susceptible to 4-NQO–induced oral carcinogenesis and more sensitive to Stattic-mediated chemoprevention compared with wild-type (WT) mice. Herein, we demonstrate that Ptprt WT and KO mice develop similar spectra of HNSCC disease severity upon 12 weeks of 4-NQO administration, with no apparent effect of Ptprt genotype on carcinogenesis or treatment outcome. Targeting of STAT3 with Stattic resulted in a chemopreventive effect against 4-NQO–induced oral cancer (P = 0.0402). While these results do not support a central role for PTPRT in 4-NQO–induced HNSCC carcinogenesis, further investigation of STAT3 as a chemoprevention target in this cancer is warranted. Cancer Prev Res; 9(8); 657–63. ©2016 AACR.

Thursday, June 30, 2016 10:05 PM|Moore, E. C., Cash, H. A., Caruso, A. M., Uppaluri, R., Hodge, J. W., Van Waes, C., Allen, C. T.|Cancer Immunology Research recent issues|Labels: mTOR, PD-1/PD-L1, pharyngeal

Significant subsets of patients with oral cancer fail to respond to single-agent programmed death (PD) blockade. Syngeneic models of oral cancer were used to determine if blocking oncogenic signaling improved in vivo responses to PD-L1 monoclonal antibody (mAb). Anti–PD-L1 enhanced durable primary tumor control and survival when combined with mTOR (rapamycin), but not in combination with MEK inhibition (PD901) in immunogenic MOC1 tumors. Conversely, PD-L1 mAb did not enhance tumor control in poorly immunogenic MOC2 tumors. Rapamycin enhanced expansion of peripheral antigen-specific CD8 T cells and IFN production following ex vivo antigen stimulation. More CD8 T cells infiltrated and were activated after PD-L1 mAb treatment in mice with immunogenic MOC1 tumors, which were stable or increased by the addition of rapamycin, but suppressed when PD901 was added. Rapamycin increased IFN production capacity in peripheral and tumor-infiltrating CD8 T cells. In vivo antibody depletion revealed a CD8 T-cell–dependent, and not NK cell–dependent mechanism of tumor growth inhibition after treatment with rapamycin and PD-L1 mAb, ruling out significant effects from NK cell–mediated antibody-dependent cellular cytotoxicity. Rapamycin also enhanced IFN or PD-L1 mAb treatment–associated induction of MHC class I expression on MOC1 tumor cells, an effect abrogated by depleting infiltrating CD8 T cells from the tumor microenvironment. These data conflict with traditional views of rapamycin as a universal immunosuppressant, and when combined with evidence of enhanced antitumor activity with the combination of rapamycin and PD-L1 mAb, suggest that this treatment combination deserves careful evaluation in the clinical setting. Cancer Immunol Res; 4(7); 611–20. ©2016 AACR.

Thursday, January 28, 2016 4:00 PM|Clinical Oral Investigations|MedWorm: Cancer Therapy|Comments|Labels: TNF, pharyngeal
Conclusions We showed for the first time that PEITC overcomes TRAIL resistance in oral cancer cells and enhance the therapeutic potential of TRAIL in vivo. Clinical relevance PEITC, either alone or in combination with TRAIL, can be used as a new therapeutic approach for the treatment of oral cancers. (Source: Clinical Oral Investigations)